Development of an Innovative Efonidipine Hydrochloride Ethanoate Co-crystals with Dicarboxylic Acids: In-Vitro, Bioavailability and Antihypertensive Properties

Abstract

Purpose

Efonidipine hydrochloride ethanolate (EHE) is a third-generation dihydropyridine calcium channel blocker, used to treat hypertension. Despite its therapeutic efficacy, EHE suffers from low aqueous solubility (less than 10 µg/mL) and oral bioavailability, which restrict its clinical impact. To address these limitations, this study employed a co-crystallization approach to enhance EHE’s solubility while maintaining its molecular structure intact.

Methods

Co-crystals of EHE with malonic acid (MA) and tartaric acid (TA) were prepared using solvent evaporation method with equimolar concentrations of EHE and the respective co-formers. The resulting malonic acid co-crystals (MAC) and tartaric acid co-crystals (TAC) were extensively characterized in terms of fourier-transform infrared spectra (FTIR), NMR, powder X-ray diffraction patterns (PXRD), differential scanning calorimetry thermogram (DSC), solubility/dissolution, and docking analysis. Further, in vivo pharmacokinetics and pharmacodynamics studies were performed in Wistar rats.

Results

The DSC, PXRD, and FTIR of MAC and TAC co-crystals unequivocally confirmed the formation of co-crystals. These co-crystals exhibited a 25- and 12-fold increase in solubility, coupled with significantly enhanced dissolution rates. Molecular docking studies indicated favorable binding energies between EHE and TA (− 0.65 kcal/mol) and MA (− 0.24 kcal/mol). Additionally, 1 H NMR spectroscopy validated the formation of a distinct phase. In bioavailability and anti-hypertensive studies conducted in Wistar rats, MAC and TAC demonstrated a 2- and 2.5-fold increase in AUC_0−∞, respectively, alongside notable reductions in mean atrial blood pressure, systolic blood pressure, and diastolic blood pressure compared to pure EHE.

Conclusion

The findings suggest that co-crystallization represents an effective strategy to enhance the dissolution rate, oral absorption, and clinical applicability of drugs with low solubility such as EHE.

Graphical Abstract